A major limitation in the use of many drugs and therapeutic agents is their inadequate ability to pass through biological barriers. This presents a serious problem especially for the treatment of diseases and disorders in privileged sites such as the central nervous system (CNS).
The blood brain barrier (BBB), made up of specialized microvascular endothelial cells connected by tight junctions, is normally responsible for maintaining the homeostatic environment of the brain and protecting it from toxic agents and degradation products present in the circulatory system. However, in certain pathological situations, the presence of the BBB may interfere with the transport of therapeutic substances into the brain, thus hampering treatment of central nervous system lesions, including tumors, infections, abscesses and degenerative diseases.
In a similar way, the presence of the blood tumor barrier (BTB) interferes with the delivery of chemotherapeutic agents into the tumor, thus decreasing drug bioavailability and preventing efficient therapeutic effect where it is needed. The problem of insufficient access of the therapeutic agent to the diseased target is especially severe in the case of CNS tumors, and patients bearing malignant brain tumors have poor prognoses.
In order to achieve clinically useful concentrations of certain drugs at restricted sites, it is often required to administer these compounds at high systemic dosages. The high systemic concentrations, in turn, are associated with adverse side effects and high levels of toxicity.
One strategy for attacking the problem involves altering the biophysical characteristics of hydrophilic drug molecules, for example, by linking these drugs to a lipophilic carrier. Since drug permeability across such biological membranes depends on its lipophilicity, increasing the lipophilic nature of the compound should, theoretically, improve its bioavailability and increase therapeutic effects. Such covalent polar lipid conjugates with neurologically active compounds for targeting are disclosed in U.S. Pat. No. 5,827,819 to Yatvin et al.
Another approach to circumvent the BBB impermeability is by employing agents that transiently open the BBB and facilitate the entry of a particular drug or agent into the brain. Agents such as mannitol have been shown to exert this desirable effect and have been employed in the delivery of chemotherapeutic agents to malignant brain tumors (Hiesinger et al. (1986), Annals of Neurology, 19:50-59). The use of this kind of hyperosmolar BBB disruption in brain tumor therapy has, however, been controversial since, in addition to the drug crossing the BBB, other molecules such as neurotoxins are also permitted entry. This may account for the high incidence of stroke, seizures, immunological reactions and ocular toxicity associated with treatment using osmotic opening methods.
A variety of other treatments have also been disclosed that increase permeability of the blood brain barrier including: the use of bradykinin agonists (W0 91/16355 of Alkermes) and certain other peptides (WO 92/18529 of Alkermes); use of bacterial cell wall fragments (WO 91/16064 of the Rockefeller Univ.) or the use of antibody to Bordetella pertussis filamentous haemagglutinin or brain endothelial x-molecule (WO 92/19269 of the Rockefeller Univ.). Certain fatty acids such as oleic acid have also been reported to reversibly open the BBB (Sztriha and Betz (1991), Brain Res. 336: 257-262).
The usefulness of methods for reversibly increasing the permeability of the blood brain barrier prior to administration of diagnostic reagents (U.S. Pat. No. 5,059,415 of the Oregon Health Sci. U.) or therapeutic reagents (WO 89/11299 of the Oregon Health Sci. U.) have been disclosed.
It was previously disclosed by the inventors of the present invention, in International patent application publication number WO 99/02120, that branched fatty acids and certain lipophilic derivatives thereof are useful for reversibly permeabilizing biomembranes. However, compounds which comprise a phosphate moiety have not been disclosed. Furthermore, it has not been disclosed that by modifying the branched fatty acids by addition of a phosphate moiety it is possible to modulate the opening of biological barriers in a specific and differential manner.
Clearly, the compositions developed so far for permeabilizing biological membranes and barriers produce severe side-effects. Therefore, there is an unmet need for providing effective and safe means for delivering adequate quantities of therapeutic and diagnostic agents into restricted sites.
Numerous compositions have been proposed for use in treating various cancers, included among them are compounds comprising a hydrocarbon chain and a phosphocholine moiety. U.S. Pat. Nos. 4,837,023 and 5,049,552, both to Eibl, disclose compositions and methods useful in treating cancer. The active material in these cases is the known substance Hexadecylphosphocholine (HePC). However, according to the disclosure in those patents, of all compounds tested only HePC possessed a practically useful anti-tumor action, while homologues with shorter alkyl radicals possessed no or much too low anti-tumor action and homologues with longer alkyl radicals were much too toxic. The prior art neither discloses nor suggests any of the compounds which are the subject matter of the present invention.